The present invention relates to a novel medical composition for topical administration showing excellent intraocular tension lowering activity.
It has been well known that angiotensin II antagonists lower intraocular tension when topically administered (EP 795326 (and U.S. Pat No. 5,925,664), EP 631780, WO 95/21609, WO 91/15206, etc.). In particular, the following compounds are known as representative drugs. 
As the result of various investigation on preparations and pharmacologies of topical compositions containing angiotensin II antagonists, the present inventors have found that the intraocular tension lowering activity of angiotensin II antagonists can be reinforced by adding one or more boric acids and one or more ethylenediamine tetraacetic acids to the composition.
The present invention relates to:
(1) an intraocular tension lowering topical composition containing an angiotensin II antagonist, a boric acid and an ethylenediamine tetraacetic acid.
Said composition preferably is
(2) a composition in which the angiotensin II antagonist is a compound of the following general formula (I) or a pharmacologically acceptable salt or derivative thereof: 
wherein R1 represents a group of the following structure (Ia), (Ib), (Ic), (Id), (Ie) or (If): 
(3) a composition in which R1 represents a group of the structure (Ia), (Ib) or (Ic);
(4) a composition in which the compound of general formula (I) is a compound selected from 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl) phenyl]phenyl}methylimidazole-5-carboxylic acid and 2-ethoxy-1-[2xe2x80x2-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl-1H-benzimidazole-7-carboxylic acid;
(5) a composition additionally containing a preservative; and
(6) a composition in which the preservative is a paraben.
Further, another object of the present invention is to provide a method of lowering intraocular tension which comprises administering a composition as described in any one of (1) to (6) above containing a pharmacologically effective amount of an angiotensin II antagonist to a warm-blooded animal (preferably human). In particular, it is to provide a method of lowering intraocular tension caused by glaucoma (including glaucoma with normal intraocular tension) or ocular hypertension.
In the present invention, xe2x80x9cboric acidxe2x80x9d includes boric acid and compounds which function equivalent to a boric acid. A substance equivalent to boric acid is a compound that gives rise to borate ion when dissolved in water. Examples of such compounds are boric anhydride (B2O3), tetraboric acid (H2B4O7), as well as pharmacologically acceptable salts of boric acid, boric anhydride, and tetraboric acid. Boric acid, boric anhydride, borax and sodium borate decahydrate are preferred. Boric acid is more preferred.
These boric acids may be used singly or in combination of two or more members.
xe2x80x9cEthylenediamine tetraacetic acidxe2x80x9d includes ethylenediamine tetraacetic acid and compounds which function equivalent to ethylenediamine tetraacetic acid. A substance equivalent to ethylenediamine tetraacetic acid is a compound that gives rise to an ethylenediamine tetraacetate ion when dissolved in water. Such compounds include pharmacologically acceptable salts of ethylenediamine tetraacetic acid, and appropriate examples thereof are ethylenediamine tetraacetic acid, disodium ethylenediamine tetraacetate dihydrate, trisodium ethylenediamine tetraacetate trihydrate, disodium ethylenediamine tetraacetate dihydrate, and tetrasodium ethylenediamine tetraacetate tetrahydrate. Disodium ethylenediamine tetraacetate dihydrate is most preferred.
These ethylenediamine tetraacetic acids may be used singly or in combination of two or more members.
xe2x80x9cAngiotensin II antagonistsxe2x80x9d preferably mean the compounds of the following general formula (I) or pharmacologically acceptable salts or derivatives thereof: 
wherein R1 represents a group of the following structures (Ia), (Ib), (Ic), (Id), (Ie) or (If): 
More preferably, the compound is 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid and 2-ethoxy-1-[2xe2x80x2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-benzimidazole-7-carboxylic acid, or a pharmacologically acceptable salt or derivative thereof.
xe2x80x9cPharmacologically acceptable saltsxe2x80x9d mean those salts that may be prepared by reacting the compound of general formula (I) above, boric acids, or ethylenediamine tetraacetic acids with a base. Examples of such salts include metal salts including alkali metal salts such as sodium salts, potassium salts, lithium salts, etc., alkaline earth metal salts such as calcium salts, magnesium salts, etc., aluminium salts and ferrous salts, etc.; amine salts including inorganic salts such as ammonium salts, etc., organic salts such as t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,Nxe2x80x2-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts, tris(hydroxymethyl)aminomethane salts, etc.; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, aspartic acid salts, etc. Of them, alkali metal salts are preferred, and sodium salts and potassium salts are more preferred.
Boric acids, ethylenediamine tetraacetic acids, and the compounds of the general formula (I) above or their pharmacologically acceptable salts may occasionally absorb water so that the absorbed water is incorporated, ie they become a hydrate, by allowing them to stand in the air or during recrystallization. Such hydrates are included in the present invention.
When the compound (i) has hydroxyl groups and/or carboxyl groups, such a compound can be converted into its derivatives by modifying those groups. So, pharmaceutically acceptable derivatives of the compound of the general formula (I) above mean such derivatives. Such derivatives include xe2x80x9cesters of hydroxyl groupsxe2x80x9d, xe2x80x9cethers of hydroxyl groupsxe2x80x9d, xe2x80x9cesters of carboxyl groupsxe2x80x9d and xe2x80x9camides of carboxyl groupsxe2x80x9d and the residues of such ester, ether or amide groups include xe2x80x9cgeneral protecting groupsxe2x80x9d or xe2x80x9cprotecting groups capable of being cleaved by biological means like hydrolysis within living bodiesxe2x80x9d.
xe2x80x9cGeneral protecting groupsxe2x80x9d mean protecting groups capable of being cleaved by chemical methods such as hydrogenation, hydrolysis, electrolysis, photolysis, etc.
xe2x80x9cGeneral protecting groupsxe2x80x9d comprising the residue of xe2x80x9cesters of hydroxyl groupsxe2x80x9d and xe2x80x9cethers of hydroxyl groupsxe2x80x9d preferably mean aliphatic acyl groups (preferably lower aliphatic acyl groups having 1 to 6 carbon atoms) including alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, heneicosanoyl, etc., halogeno-alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, etc., lower alkoxyalkylcarbonyl groups such as methoxyacetyl, etc., unsaturated alkylcarbonyl groups such as acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl etc.; aromatic acyl groups including arylcarbonyl groups such as benzoyl, xcex1-naphthoyl, xcex2-naphthoyl, etc., halogenoarylcarbonyl groups such as 2-bromobenzoyl, 4-chlorobenzoyl, etc., lower alkylarylcarbonyl groups such as 2,4,6-trimethylbenzoyl, 4-toluoyl, etc., lower alkoxyarylcarbonyl groups such as 4-anisoyl, etc., nitroarylcarbonyl groups such as 4-nitrobenzoyl, 2-nitrobenzoyl, etc., lower alkoxycarbonylarylcarbonyl groups such as 2-(methoxycarbonyl)benzoyl, etc. and arylarylcarbonyl groups such as 4-phenylbenzoyl, etc.; alkoxycarbonyl groups including lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, etc., lower alkoxycarbonyl groups substituted with halogen atoms or tri-lower alkylsilyl groups such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc; tetrahydropyranyl or tetrahydrothiopyranyl groups such as tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl-4-methoxytetrahydrothiopyran-4-yl, etc.; tetrahydrofuranyl or tetrahydrothiofuranyl groups such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl, etc.; silyl groups including tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, etc., tri-lower alkylsilyl groups where 1 or 2 of the alkyl groups are replaced by 1 or 2 aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl, etc; alkoxymethyl groups including lower alkoxymethyl groups such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, etc., lower alkoxy-lower alkoxymethyl groups such as 2-methoxyethoxymethyl, etc., halogeno lower alkoxymethyl groups such as 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, etc.; substituted ethyl groups including lower alkoxyethyl groups such as 1-ethoxyethyl, 1-(isopropoxy)ethyl, etc., halogenoethyl groups such as 2,2,2-trichloroethyl, etc.; aralkyl groups including lower alkyl groups (such as C1-C6 straight or branched chain alkyl, preferably methyl, ethyl, propyl, isopropyl or butyl, and more preferably methyl or ethyl), substituted with 1 to 3 aryl groups such as benzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl, diphenylmethyl, triphenylmethyl, xcex1-naphthyldiphenylmethyl, 9-anthrylmethyl, etc., lower alkyl groups substituted with 1 to 3 aryl groups where said aryl group is substituted with one or more lower alkyl, lower alkoxy (such as C1-C4 straight or branched chain alkoxy, preferably methoxy, ethoxy, propoxy, isopropoxy or butoxy, and more preferably methoxy or ethoxy), nitro, halogen or cyano groups, e.g. 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyidiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, etc.; alkenyloxycarbonyl groups such as vinyloxycarbonyl, allyloxycarbonyl, etc.; and aralkyloxycarbonyl groups where said aryl group may be substituted with 1 or 2 lower alkoxy or nitro groups, e.g. benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.
xe2x80x9cGeneral protecting groupsxe2x80x9d comprising the residue of xe2x80x9cesters of carboxyl groupsxe2x80x9d preferably mean lower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimetlhylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, etc.; lower alkenyl groups such as vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl4-pentenyl, 2-methyl4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, etc.; lower alkynyl groups such as ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1 ethyl-3-butynyl 2pentynyl, 1methyl 2-pentynl-3-pentynyl, 4-pentynyl 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc.; halogeno lower alkyl groups such as trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, etc.; hydroxy lower alkyl groups such as 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihyidroxybutyl, 4-hydroxybutyl, etc.; lower aliphatic acyl - lower alkyl groups such as acetylmethyl, etc.; aralkyl groups mentioned above; and silyl groups mentioned above.
xe2x80x9cProtecting groups capable of being cleaved by biological means like hydrolysis within living bodiesxe2x80x9d mean protecting groups which can be cleaved by hydrolysis or the like within living bodies to yield the original compound or its pharmacologically acceptable salt. Whether a group is a xe2x80x9cprotecting group capable of being cleaved by biological means like hydrolysis within living bodiesxe2x80x9d or not can be determined by administering such a derivative by intravenous injection into test animals such as rats or mice, examining the body liquid thereafter and detecting the original compound or its pharmacologically acceptable salt.
xe2x80x9cProtecting groups capable of being cleaved by biological means like hydrolysis within living bodiesxe2x80x9d comprising the residue of xe2x80x9cesters of hydroxyl groupsxe2x80x9d and xe2x80x9cethers of hydroxyl groupsxe2x80x9d preferably mean carbonyloxyalkyl groups, for example, 1-(acyloxy)lower alkyl groups including 1-(lower aliphatic acyloxy)-lower alkyl groups such as formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl, etc., 1-(cycloalkyl-carbonyloxy)-lower alkyl groups such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl, etc., 1-(aromatic acyloxy)-lower alkyl groups such as benzoyloxymethyl, etc.; lower alkoxycarbonyloxy)alkyl groups such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)ethyl, 1-(isobutoxycarbonyloxy)ethyl, 1-(t-butoxycarbonyloxy)ethyl, 1-(pentyloxycarbonyloxy)ethyl, 1-(hexyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, 1-(cyclopentyloxycarbonyloxy)propyl, 1-(cyclohexyloxycarbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)butyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)propyl, 1-(ethoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)propyl, 1-(isopropoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)propyl, 1-(isobutoxycarbonyloxy)propyl, 1-(pentyloxycarbonyloxy)propyl, 1-(hexyloxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)butyl, 1-(propoxycarbonyloxy)butyl, 1-(isopropoxycarbonyloxy)butyl, 1-(butoxycarbonyloxy)butyl, 1-(isobutoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)pentyl, 1-(methoxycarbonyloxy)hexyl, 1-(ethoxycarbonyloxy)hexyl, etc.; oxodioxolenylmethyl groups such as (5-phenyl-2-oxo-1,3-dioxolen4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxolen4-yl]methyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1,3-dioxolen4-yl]methyl, (2-oxo-1,3-dioxolen4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen4-yl)methyl, (5-butyl-2-oxo-1,3-dioxolen4-yl)methyl, etc.; phthalidyl groups such as phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl, etc.; lower aliphatic acyl groups mentioned above; aromatic acyl groups mentioned above; residues of a succinic acid half ester salt; residues of a phosphoric acid ester salt; residues of ester-forming groups such as amino acids; carbamoyl groups; carbamoyl groups substituted with 1 or 2 lower alkyl groups; and 1-(acyloxy)alkyloxycarbonyl groups such as pivaloyloxymethyloxycarbonyl, etc. Carbonyloxyalkyl groups are preferred.
On the other hand, xe2x80x9cprotecting groups capable of being cleaved by biological means like hydrolysis within living bodiesxe2x80x9d comprising the residue of xe2x80x9cesters of carboxy groupsxe2x80x9d preferably mean alkoxy-lower alkyl groups including lower alkoxy-lower alkyl groups such as methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, etc., lower alkoxy-lower alkoxy-lower alkyl groups such as 2-methoxyethoxymethyl, etc., aryloxy-lower alkyl groups such as phenoxymethyl, etc., (halogeno lower alkoxy)-lower alkyl groups such as 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, etc.; (lower alkoxy-carbonyl)lower alkyl groups such as methoxycarbonylmethyl, etc,; cyano-lower alkyl groups such as cyanomethyl, 2-cyanoethyl, etc.; (lower alkyl)thiomethyl groups such as methylthiomethyl, ethylthiomethyl, etc.; arylthiomethyl groups such as phenylthiomethyl, naphthylthiomethyl, etc.; (optionally halogenated lower alkyl)-sulfonyl lower alkyl groups such as 2-methanesulfonylethyl, 2-trifluoromethanesulfonylethyl, etc.; (aryl sulfonyl)-lower alkyl groups such as 2-benzenesulfonylethyl, 2-tolenesulfonylethyl, etc.; 1-(acyloxy)-lower alkyl groups mentioned above; phthalidyl groups mentioned above; lower alkyl groups mentioned above; carboxyalkyl groups such as carboxymethyl, etc.; and residues of amide-forming groups of amino acidsxe2x80x9d such as phenylalanine, etc.
The intraocular tension lowering composition for topical administration of the present invention can be prepared in a conventional manner by using one or more angiotensin II antagonists, one or more boric acids and one or more ethylenediamine tetraacetic acids. For example, the ophthalmic composition can be used in a formulation suitable for topical administration such as eye drops e.g. aqueous eye drops, aqueous ophthalmic suspensions, non-aqueous eye drops and non-aqueous ophthalmic suspensions, gels, ophthalmic ointments, etc. For preparing such formulations, pharmacologically acceptable carriers may be added to said ingredients. No limitation is given to the carriers to be used if they are those customarily applied to ophthalmic formulations, and they illustratively include inert diluents, preservatives, isotonic agents, buffering agents, pH regulating agents, thickeners, surfactants, ointment bases, and the like.
Examples of inert diluents include aqueous solvents such as water, Ringer solution, isotonic saline, etc. or oily solvents such as castor oil, olive oil, sesame oil, soybean oil, liquid paraffin, propylene glycol, xcex2-octyldodecanol, etc.
Examples of preservatives include parabens such as methylparaben, ethylparaben, propylparaben, butylparaben, etc., benzalkonium chloride, chlorohexidine, benzethonium chloride, benzyl alcohol, sorbic acid and its salts, thimerosal, chlorobutanol, etc. Parabens, benzalkonium chloride and benzethonium chloride are preferred.
Since excellent preservative effects can be attained by using boric acids and ethylenediamine tetraacetic acids together with parabens, the parabens are most preferred.
Examples of isotonic agents are sodium chloride, mannitol, sorbitol, glycerin, etc.
Examples of buffering agents are phosphates, acetates, citrates, etc.
Examples of pH regulating agents are hydrochloric acid, acetic acid, sodium hydroxide, and the like.
Examples of ointment bases are vaseline, plastibase (trade mark), liquid paraffin, etc.
Examples of thickeners are methyl cellulose, carmelose and its salts, hydroxyethyl cellulose, sodium alginate, carboxy vinyl polymer, polyvinylpyrrolidone, and the like.
Examples of surfactants are polyethylene glycol, polypropylene glycol, polyoxyethylene hardened castor oil, polysorbate, etc.
For preparing a gel, for example, carboxyvinyl polymer, methyl cellulose, sodium alginate, hydroxypropyl cellulose, ethylene maleic anhydride polymer and the like can be used.
Concerning the formulation of the topical composition of the present invention, a lower amount of the angiotensin II antagonist is 0.001% (preferably 0.01%) and an upper amount is 10% (preferably 5%).
For the amount of the boric acid compound in the composition, a lower amount is suitably 0.05% (preferably 0.1%, and more preferably 0.5%) and an upper amount is suitably 10% (preferably 5%, and more preferably 2%), calculated as boric acid.
For the amount of the ethylenediamine tetraacetic acid compound in the composition, a lower amount is suitably 0.00025% (preferably 0.0005%, and more preferably 0.005%) and an upper amount is suitably 0.2% (preferably 0.1%, and more preferably 0.05%), calculated as disodium ethylenediamine tetraacetate dihydrate.
The above percents are each a percent by weight (in grams) of the component per 100 ml of the volume of the total pharmacological (ophthalmic) composition, namely w/v %. Thus, xe2x80x9c1%xe2x80x9d equals 0.01 g/mL which equals 1 g/100 mL.
The relative amounts of the boric acid compound and the ethylenediamine tetraacetic acid compound follow: The lower weight ratio of the amount of the ethylenediamine tetraacetic acid compound (calculated as noted above) relative to the boric acid compound (calculated as noted above) is suitably 0.00025:1 (preferably 0.0005:1 and more preferably 0.005:1); and the upper ratio is suitably 0.2:1 (preferably 0.1:1 and more preferably 0.05:1).
The dose of the composition of the present invention differs, depending upon the patient""s (e.g., human) condition. When the composition of the present invention is used as eye drops, for example, one to several drops per unit dose, preferably 1 or 2 drops (about 50 xcexcL per 1 drop), are applicable about 1 to about 6 times daily. Although the method of the present invention preferably applies the combination of the three active components in the form of a composition, the three active components may also be applied separately but substantially simultaneously to an eye. The references herein to lower intraocular tension refers to lowering of intraocular pressure.
The composition and method of the present invention may be applied to an eye of a warm-blooded animal, and particularly a human.
A concrete description of the present invention will now be illustrated by the following Examples and Experiments, but the scope of the present invention is not limited thereby.